Towards Safer and More Effective CART Cell Therapy Through the Modulation of Myeloid Cytokines

通过调节骨髓细胞因子实现更安全、更有效的 CART 细胞疗法

• 批准号: 10867998
• 负责人: Saad J. Kenderian
• 金额: $ 47.5万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-09 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10867998
• 关键词: Address; Allogenic; Autologous; B lymphoid malignancy; B-Lymphocytes; Biological Models; Blood Component Removal; CAR T cell therapy; Canis familiaris; Cell Therapy; Cells; Clinical; Clinical Trials; Collaborations; Companions; Development; Diameter; Disease; Disease model; Disease remission; Engineering; Enrollment; FDA approved; Fine needle aspiration biopsy; Functional disorder; Generations; Goals; Hematologic Neoplasms; Human; Human Engineering; Image; Infusion procedures; Lymphoma; MS4A1 gene; Measurement; Measures; Modeling; Monitor; Mus; Myelogenous; Non-Hodgkin' s Lymphoma; Oncologist; Outcome; Patients; Pilot Projects; Positron-Emission Tomography; Publishing; Regimen; Reporter; Resistance; SLC5A5 gene; Sampling; Serum; Signal Transduction; Site; Solid Neoplasm; Sum; Symptoms; System; T-Lymphocyte; Techniques; Testing; Time; Toxic effect; Transgenes; Translations; Visualization; Work; alpha-beta T-Cell Receptor; analog; beta-2 Microglobulin; cancer therapy; chimeric antigen receptor; chimeric antigen receptor T cells; clinical predictors; cytokine; cytokine release syndrome; design; first-in-human; graft vs host disease; immunogenicity; in vivo; in vivo imaging; interest; large cell Diffuse non-Hodgkin' s lymphoma; lymph nodes; manufacture; mouse model; neurotoxicity; novel; novel strategies; peripheral blood; pre-clinical; preclinical study; prevent; response; safety testing; success; therapy development; trafficking; tumor; tumor microenvironment

PROJECT SUMMARY Despite the impressive activity of chimeric antigen receptor T (CART) cell therapy in the treatment of B-cell malignancies, the therapy is limited by the development of toxicities, including cytokine release syndrome (CRS) and neurotoxicity, as well as by lower rates of durable responses. The in vivo expansion of CART cells is a critical determinant of their antitumor activity as well as of the development of toxicities. Over the last 5 years, we have focused our work on addressing limitations related to CART complexity, toxicity, and resistance. We utilized companion dogs as a proof-of-concept model to test engineered allogeneic human CART cells as a therapy for spontaneous disease including diffuse large B-cell lymphoma (DLBCL). We engineered canine CD20-targeting xenogeneic human CART cells (T-cell receptor alpha (TRAC)- and beta-2 microglobulin (B2M)- disrupted), developed and optimized a canine-specific lymphodepleting regimen, and tested the safety of xenogeneic CART cells in healthy beagles. Then, to track CART cell fates and functions in real time in vivo, we developed and recently published the utility of sodium iodide symporter (NIS) as a platform to detect CART cell expansion, trafficking, and toxicity in mouse models. In this application, we propose to utilize our NIS reporter system, novel canine lymphodepletion regimen, and established canine clinical trial expertise to test NIS+ human CART cells in companion dogs. We hypothesize that 18F-tetrafluoroborate (TFB) PET imaging of NIS+ canine CD20-targeting xenogeneic human CART cells is a sensitive strategy to detect CART cell rejection, expansion, and trafficking to tumor sites in canine patients with DLBCL. To test this hypothesis, we have designed two specific aims. In Aim 1, we will study the utility of TFB-PET imaging of NIS+ CART cells to measure CART expansion, rejection, and trafficking in canine patients with DLBCL. We will determine how quantitative PET signal (qPET) correlates with quantitative PCR (qPCR) measurement of the CAR transgene in peripheral blood and lymph node samples. In Aim 2, we will determine how TFB-PET imaging of CART cell expansion and trafficking correlates with their activity and toxicity. Completion of these aims will validate qPET imaging as a non-invasive platform to study CART dynamics in canine lymphoma and provide additional rationale to propose a first-in-human clinical trial of NIS+ CART cells in patients with lymphoma.

项目摘要 尽管嵌合抗原受体T（CART）细胞治疗在B细胞治疗中具有令人印象深刻的活性 恶性肿瘤，该疗法受到毒性发展的限制，包括细胞因子释放综合征（CRS） 和神经毒性，以及耐用响应速率较低。 CART细胞的体内扩展是 其抗肿瘤活性以及毒性发展的关键决定因素。在过去的五年中， 我们将工作重点放在解决与CART复杂性，毒性和抗性有关的局限性上。我们 利用伴侣犬作为概念验证模型，以测试工程化的同种人口车细胞 自发疾病的治疗，包括弥漫性大B细胞淋巴瘤（DLBCL）。我们设计了犬科 CD20靶向异构人类推车细胞（T细胞受体α（TRAC） - 和β-2微球蛋白（B2M） - 被破坏），开发和优化了犬特异性淋巴结治疗方案，并测试了 健康蛋糕中的异构推车细胞。然后，为了在体内实时跟踪CART单元格的命运和功能，我们 开发并最近发表了碘化钠对孢子（NIS）的效用，作为检测购物车细胞的平台 小鼠模型中的扩展，运输和毒性。在此应用程序中，我们建议利用我们的NIS记者 系统，新型犬淋巴结治疗方案，并建立了犬临床试验专业知识，以测试NIS+人类 伴侣犬中的手推车细胞。我们假设NIS+犬的18F-Tet​​rafluorobare（TFB）PET成像 CD20靶向异构人类手推车细胞是检测CART细胞排斥，扩张， 并贩运DLBCL犬类患者的肿瘤部位。为了检验这一假设，我们设计了两个 具体目标。在AIM 1中，我们将研究NIS+ CART细胞的TFB-PET成像的实用性 DLBCL患者的扩张，排斥和贩运。我们将确定定量宠物如何 信号（QPET）与周围血液中CAR转基因的定量PCR（QPCR）测量相关 和淋巴结样品。在AIM 2中，我们将确定CART细胞扩展的TFB-PET成像和 贩运与其活动和毒性相关。这些目标的完成将验证QPET成像为 非侵入性平台研究犬淋巴瘤中的卡车动力学，并提供额外的理由来提出 NIS+ CART细胞在淋巴瘤患者中的首次人类临床试验。

项目成果

Who wins the combat, CAR or TCR?

• DOI: 10.1038/s41375-023-01976-z
• 发表时间: 2023-08
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Kun Yun;Elizabeth L. Siegler;S. Kenderian

Assessment of Chimeric Antigen Receptor T Cell-Associated Toxicities Using an Acute Lymphoblastic Leukemia Patient-derived Xenograft Mouse Model.

使用急性淋巴细胞白血病患者来源的异种移植小鼠模型评估嵌合抗原受体 T 细胞相关毒性。

• DOI: 10.3791/64535
• 发表时间: 2023
• 期刊: Journal of visualized experiments : JoVE
• 作者: ManriquezRoman,Claudia;Sakemura,RLeo;Kimball,BrookeL;Jin,Fang;Khadka,RomanH;Adada,MohamadM;Siegler,ElizabethL;Johnson,AaronJ;Kenderian,SaadS
• 通讯作者: Kenderian,SaadS